ABSTRACT Patients with acute coronary syndromes (ACS) who are diagnosed with major depression are at greater risk for subsequent major adverse coronary events (MACE). Major depression is associated with increased inflammatory protein levels, but only in certain individuals. In a prospective cohort study of ACS patients, with a nested case-control component, we propose to test a biobehavioral model in which major depression interacts with inflammatory protein gene polymorphisms resulting in even greater increases in inflammatory protein levels than those caused by either depression or gene polymorphisms alone. We expect to identify a well-defined, high-risk subgroup of ACS patients in which the interaction of depression and the genetic polymorphisms identified increases risk of subsequent MACE (myocardial infarctions, revascularization procedures, strokes, and death) more than does either of these factors alone, in part because of their combined effect of increasing inflammatory proteins. Inflammatory proteins and genes measured include: Interleukin (IL) 6, C-reactive Protein (CRP), Tumor Necrosis Factor Alpha (TNF?), E-Selectin (SELE), and Monocyte Chemoattractant Protein-1 (MCP-1). Major depression, inflammatory protein levels and genotype from patients who are positive for subsequent major adverse coronary events (MACE) (cases) during the 12 month study will be compared with these factors from subjects who are negative for MACE (controls). To test these hypotheses, eligible patients from a single large tertiary care center will be identified, consented, and enrolled into the study during their hospitalization for ACS. Blood samples for genes will be collected once only;whereas inflammatory protein measurements, depression, and confounding factor data will be collected at 6-8 weeks and 7 months after hospital discharge. At 12 months, follow-up data for MACE will be collected by telephone interview. The Depression Interview and Structured Hamilton (DISH) will be used to diagnose major depression. Data will be analyzed using multiple logistic regression. PUBLIC HEALTH RELEVANCE The discovery of a relationship among depression, genetics, inflammatory protein levels, and subsequent MACE in an ACS subgroup would provide a rationale for studying environmental triggers of depression and the effects of depression interventions (different medications, psychotherapies, combinations of treatment, and self-management techniques such as exercise) on inflammatory protein levels for their effects on future MACE. The ability to decrease mortality and morbidity in ACS patients would benefit public health efforts, particularly efforts to improve the health of older persons, who are more prone to coronary events.